Project Summary/Abstract The goal of this proposal is to validate glycated CD59 in human blood (GCD59) as a screening test to identify individuals with pre-diabetes, and an early bio-marker of diabetes complications focusing on diabetic neuropathy. This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects ? 25 million Americans, 2) diabetes complications are a major cause of morbidity and mortality in the U.S., and 3) treatment of these complications costs a staggering 245 billion dollars/year (expected to rise to >300 billion by 2034). HbA1c, the clinical gold standard for management of patients with diabetes, does not identify individuals at higher risk of developing some complications and is not sensitive enough to clearly discriminate individuals with pre-diabetes. Chronic hyperglycemia is ultimately responsible for the complications of human diabetes but the cellular and molecular mechanism(s) by which hyperglycemia causes tissue damage are still poorly understood. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement system and the pathogenesis of the complications of diabetes, and 3) developed key reagents that allow quantification of GCD59 in blood and tissues. Specifically, we have demonstrated that 1) GCD59 is present in target organs of diabetic complications, and 2) GCD59 can be readily measured in normal plasma or serum. Furthermore, our preliminary data show that GCD59 is a) significantly increased in the blood of individuals with diabetes or pre-diabetes as well as in pregnant women with gestational diabetes mellitus, b) is a strong and independent predictor of glucose tolerance determined by standard 2hr oral glucose tolerance test, and c) seems to respond faster than HbA1c to changes in glycemic load within an individual All necessary tools and expertise to accomplish our aims are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for GCD59 and assay calibrators, access to large and diverse population of individuals with and without diabetes, and diagnostic tools, equipment and expertise necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in diagnosis, treatment and prevention of the devastating complications of glucose dysmetabolism and diabetes, and should help lower the extremely high costs derived from diabetes and its complications.